The present invention relates to therapeutically active 7-oxo-2azabicyclo[2.2.1]heptanes, the compounds of formula I, and pharmaceutical compositions thereof. The compounds of formula I are muscarinic receptor modulators. More specifically, the compounds of the present invention are agonists of the muscarinic M-4 receptor. As such they are useful for the treatment of various diseases and conditions. The present invention relates to the use of the compounds of formula I to treat diseases and conditions treated by muscarinic receptor modulators, for example, Alzheimer""s disease, glaucoma, mania, bipolar disorder, depression, sleeping disorders, epilepsy, gastrointestinal motility disorders, urinary incontinence, pain, psychosis, particularly schizophrenia or schizophreniform conditions, and cognition enhancement, such as enhancement of learning, association, consolidation, and recognition. The present invention also relates to processes for the preparation of the compounds of formula I and intermediates thereof.
Compounds which interact with muscarinic receptors are known in the art. In particular, certain oxo-2-azabicycloalkane containing compounds are described as muscarinic receptor modulators in PCT Publication No. WO 96/12711, published May 2, 1996.
The present invention relates to compounds of formula I 
wherein
X is oxygen or sulfur;
R is hydrogen, phenyl, substituted phenyl, xe2x80x94OR2, xe2x80x94SR2, xe2x80x94SOR2, xe2x80x94SO2R2 
wherein R2 is C1-C10 alkyl, C3-C10 alkenyl, C3-C10 alkynyl, substituted with from 1 to 3 substituents selected from the group consisting of hydrogen, halogen, xe2x80x94CF3, xe2x80x94CN, phenyl, substituted phenyl, phenoxy, substituted phenoxy, thiophenoxy, substituted thiophenoxy, C3-C8 cycloalkyl, heterocycle, and xe2x80x94Z-heterocycle, wherein Z is oxygen or sulfur;
R1 is selected from the group consisting of hydrogen, C1-C5 alkyl, C2-C5 alkenyl and C2-C5 alkynyl;
or a pharmaceutically acceptable salt thereof.
Also, the present invention provides pharmaceutical compositions comprising a compound of formula I and a pharmaceutically acceptable diluent.
The present invention further provides a method of treating diseases and conditions treated by muscarinic receptor modulators in a patient in need thereof comprising administering to the patient an effective amount of a compound of formula I or pharmaceutically-acceptable addition salt thereof. Such diseases and conditions treated by muscarinic receptor modulators include Alzheimer""s disease, glaucoma, mania, bipolar disorder, depression, sleeping disorders, epilepsy, gastrointestinal motility disorders, urinary incontinence, pain, psychosis, particularly schizophrenia or schizophreniform conditions, and cognition enhancement, such as enhancement of learning, association, consolidation, and recognition. Since the present compounds are muscarinic M-4 agonists they are particularly useful for treating pain and Alzheimer""s disease and providing cognitive enhancement.
As used herein, the following terms have the meanings indicated:
the term xe2x80x9csubstituted phenylxe2x80x9d refer to a radical of the formula 
xe2x80x83wherein Ra is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 thioalkoxy, xe2x80x94CF3, xe2x80x94CN, and phenyl;
the term xe2x80x9chalogenxe2x80x9d refers to a chlorine atom, bromine atom, or an iodide atom;
the term xe2x80x9cC1-C10 alkylxe2x80x9d refers to a straight or branched chain alkyl having from one to ten carbon atoms and includes, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pentyl, hexl, heptyl, octyl, nonyl, decyl, and the like;
the term xe2x80x9cC3-C10 alkenylxe2x80x9d refers to a straight or branched chain alkenyl having from three to ten carbon atoms containing at least one double-bond and includes, allyl, but-2-enyl, but-3-enyl, 3-methylbut-3-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, hexenyl, heptenyl, octenyl, nonenyl, docenyl, and the like;
the term xe2x80x9cC3-C10 alkynylxe2x80x9d refers to an unsaturated branched or linear group having from three to ten carbon atoms and at least one triple bond and includes, propargyl, but-2-ynyl, but-3-ynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like;
the term xe2x80x9cC3-C8 cycloalkylxe2x80x9d refers to a saturated or unsaturated cyclic alkyl group having from three to eight carbon atoms and from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 thioalkoxy, xe2x80x94CF3, xe2x80x94CN, and phenyl and includes, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl and the like, and includes cylcoalkyl groups in which one of the carbon atoms of the cycloalkyl is part of the C1-C10 alkyl, C3-C10 alkenyl, or C3-C10 alkynyl to which it is attached and includes cyclic alkyl groups having a fused phenyl group as part of the ring;
the term xe2x80x9csubstituted phenoxyxe2x80x9d refers to a radical of the formula 
wherein Rb is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 thioalkoxy, xe2x80x94CF3, xe2x80x94CN, and phenyl;
the term xe2x80x9csubstituted thiophenoxyxe2x80x9d refers to a radical of the formula 
wherein Rb is from 1 to 2 substituents independently selected from the group consisting of hydrogen, halogen, C1-C5 alkyl, C1-C5 alkoxy, C1-C5 thioalkoxy, xe2x80x94CF3, xe2x80x94CN, and phenyl;
the term xe2x80x9cheterocyclexe2x80x9d refers to a 5 or 6 membered heterocyclic group containing from one to four heteroatoms independently selected for the group consisting of N, O, and S atom(s), which heterocycle is optionally benzofused and is optionally substituted at its nitrogen atoms, if present, with C1-C5 alkyl, phenyl, and benzyl and is optionally substituted at its carbon atoms with C1-C5 alkyl, C1-C5 alkoxy, C1-C5 thioalkoxy, halogen, xe2x80x94CF3, phenyl, benzyl or thienyl; the term includes, 5-membered heterocycles having one heteroatom, for example, thiophenes, pyrroles, furans, benzothiophenes, indoles, benzofurans, and the like; 5-membered heterocycles having two heteroatoms, for example, oxazoles, isoxazoles, pyrazoles, imidazoles, thiazoles, isothiazoles, benzoxazoles, benzopyrazoles, benzimidazoles, benzothiazoles, and the like; 5-membered heterocycles having three heteroatoms, for example, triazoles, thiadiazoles, furazans, and the like; 6-membered heterocycles with one heteroatom, for example, pyridine, quinoline, isoquinoline, and the like; 6-membered heterocycles with two heteroatoms, for example, pyrazines, pyrimidines, pyridazines, quinazolines, dioxanes, quinazolines, cinnolines, benzodioxanes, and the like;
the term xe2x80x9cC1-C5 alkylxe2x80x9d refers to a straight or branched chain alkyl having from one to five carbon atoms and includes, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, t-butyl, pentyl, and the like;
the term xe2x80x9cC3-C5 alkenylxe2x80x9d refers to a straight or branched chain alkenyl having from three to five carbon atoms containing at least one double-bond and includes, allyl, 3-methyl-prop-2-enyl, but-2-enyl, but-3-enyl, pent-2-enyl, pent-3-enyl, pent-4-enyl, and the like;
the term xe2x80x9cC3-C5 alkynylxe2x80x9d refers to an unsaturated branched or linear group having from three to five carbon atoms and at least one triple bond and includes, propargyl, but-2-ynyl, but-3-ynyl, pentynyl and the like;
the term xe2x80x9cC1-C5 alkoxyxe2x80x9d refers to a straight or branched chain alkoxy having from one to five carbon atoms and includes, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, iso-butoxy, t-butoxy, pentoxy, and the like;
the term xe2x80x9cC1-C5 thioalkoxyxe2x80x9d refers to a straight or branched chain thioalkoxy having from one to five carbon atoms and includes, thiomethoxy, thioethoxy, thiopropoxy, thiobutoxy, thiopentoxy, and the like; and the term xe2x80x9cpharmaceutically-acceptable addition saltxe2x80x9d refers to an acid addition salt.
The compound of formula I and the intermediates described herein form pharmaceutically acceptable acid addition salts with a wide variety of organic and inorganic acids and include the physiologically acceptable salts which are often used in pharmaceutical chemistry. Such salts are also part of this invention. A pharmaceutically-acceptable addition salt is formed from a pharmaceutically-acceptable acid as is well known in the art. Such salts include the pharmaceutically acceptable salts listed in Journal of Pharmaceutical Science, 66, 2-19 (1977) which are known to the skilled artisan. Typical inorganic acids used to form such salts include hydrochloric, hydrobromic, hydriodic, nitric, sulfuric, phosphoric, hypophosphoric, metaphosphoric, pyrophosphoric, and the like. Salts derived from organic acids, such as aliphatic mono and dicarboxylic acids, phenyl substituted alkanoic acids, hydroxyalkanoic and hydroxyalkandioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, may also be used. Such pharmaceutically acceptable salts thus include acetate, phenylacetate, trifluoroacetate, acrylate, ascorbate, benzoate, chlorobenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate, o-acetoxybenzoate, naphthalene-2-benzoate, bromide, isobutyrate, phenylbutyrate, xcex1-hydroxybutyrate, butyne-1,4-dicarboxylate, hexyne-1,4-dicarboxylate, caprate, caprylate, cinnamate, citrate, formate, fumarate, glycollate, heptanoate, hippurate, lactate, malate, maleate, hydroxymaleate, malonate, mandelate, mesylate, nicotinate, isonicotinate, nitrate, oxalate, phthalate, teraphthalate, propiolate, propionate, phenylpropionate, salicylate, sebacate, succinate, suberate, benzene-sulfonate, p-bromobenzenesulfonate, chlorobenzenesulfonate, ethanesulfonate, 2-hydroxyethanesulfonate, methanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, p-toluenesulfonate, xylenesulfonate, tartarate, and the like.
As is appreciated by the skilled person, compounds of formula I exist as stereoisomers. The present invention relates to the stereoisomers of the compounds of formula I. Herein, the Cahn-Prelog-Ingold designations of (R)xe2x80x94 and (S)xe2x80x94 are used to refer to specific isomers where designated. Herein, the designations endo- and exo- are used to designate the relative spatial relationship between the 7-postion and the 2-aza function of the 2-aza-bicyclo[2.2.1]heptane.
The specific endo- and exo-isomers are shown below: 
The specific isomers can by prepared by stereospecific synthesis or can be resolved and recovered by techniques known in the art, such as, chromatography on chiral stationary phases, and fractional recrystallization of addition salts formed by reagents used for that purpose. Useful methods of resolving and recovering specific stereoisomers are known in the art and described in Stereochemistry of Organic Compounds, E. L. Eliel and S. H. Wilen (Wiley-Interscience 1994), Enantiomers, Racemates, and Resolutions, J. Jacques, A. Collet, and S. H. Wilen (Wiley-Interscience 1981), and European Patent Application No. EP-A-838448, published Apr. 29, 1998.
It is to be understood that the invention extends to each of the isomeric forms of the compounds of the present invention including the geometric, diastereomeric, enantiomeric, and racemic forms of the compound of formula I.
As with any group of pharmaceutically active compounds, some groups are preferred in their end use application.
Preferred embodiments of the present invention are given below:
Compounds wherein X is sulfur are preferred.
Compound wherein R1 is hydrogen are preferred.
Compounds wherein R is xe2x80x94OR2 or xe2x80x94SR2 are preferred.
Compounds wherein R is xe2x80x94OR2 or xe2x80x94SR2 and R2 is C1-C10 alkyl are preferred.
Compounds wherein R is xe2x80x94OR2 or xe2x80x94SR2 and R2 is C1-C10 alkyl substituted with phenyl or substituted phenyl are preferred.
Compounds wherein R is xe2x80x94OR2 or xe2x80x94SR2 and R2 is C1-C10 alkyl substituted with a heterocycle selected from the group consisting of thienyl, furanyl, pyridyl, and benzodioxanyl are preferred.
Compounds having the endo-configuration are most preferred.
Examples of compounds encompassed by the present invention include the following. This list is meant to be representative only and in not intended to limit the scope of the invention in any way:
Endo-2-aza-7-(4-methoxy-1,2,5-thiadiazol-3-yl)oxy)bicyclo[2.2.1]heptane;
Endo-2-aza-7-(4-ethoxy-1,2,5-thiadiazol-3-yl)oxy)bicyclo[2.2.1]heptane;
Endo-2-aza-7-(4-thiomethoxy-1,2,5-thiadiazol-3-yl)oxy)bicyclo[2.2.1]heptane;
Endo-2-aza-7-(4-thioethoxy-1,2,5-thiadiazol-3-yl)oxy)bicyclo[2.2.1]heptane; and
Endo-2-aza-7-(4-thiobenzyl-1,2,5-thiadiazol-3-yl)oxy)bicyclo[2.2.1]heptane.
The compounds of formula I are prepared as described in Reaction Schemes A.1 and A.2 below. In Reaction Scheme A.1 and A.2, all substituents, unless otherwise indicated, are as previously defined. In Reaction Scheme A.1 and A.2 all reagents are well known and appreciated in the art. 
In Reaction Scheme A.1, step axe2x80x2, depicts the reaction of a suitable alcohol of formula (1) and a suitable compound of formula (axe2x80x2) to give a compound of formula Ixe2x80x2. A suitable compound of formula (1) is one in which Pg is a suitable protecting group and R1 is as desired in the final product or gives rise upon alkylation to R1 as desired in the final product of formula I. A suitable compound of formula (1) may also one which has the stereochemistry as desired in the final compound of formula I or one which give rise to the stereochemistry as desired in the final compound of formula I. Suitable protecting group for amines are well known in the art and include benzyl, alkyl substituted benzyl, such as xcex1-methylbenzyl, and carbamates such as benzyloxycarbonyl and t-butoxycarbonyl. A suitable compound of formula (axe2x80x2) is one in which R is as desired in the final product of formula I or gives rise upon sulfide oxidation to R as desired in the final product of formula I. A suitable compound of formula (axe2x80x2) is also one in which Y is a leaving group or a hydroxy group.
For example, a metal alkoxide of a compound of formula (1) and a compound of formula (axe2x80x2) in which Y is a leaving group are contacted to give a compound of formula Ixe2x80x2. Suitable compounds of formula (axe2x80x2) having leaving groups, Y, such as chloro, bromo, iodo, alkylsulfonyl, and the like. The preparation of compounds of formula (axe2x80x2) in which Y is a leaving group is well known and appreciated in the art. For example see U.S. Pat. No. 5,821,370 which is hereby incorporated by reference, PCT Publication No. WO 98/54151, published Dec. 3, 1998, and J. Med. Chem., 41, 379-392 (1998). While many metals are suitable for this reaction, generally, an alkali metal alkoxide is used, with the lithium, sodium, and potassium alkoxide being preferred. The alkoxide is formed by contacting of an alcohol of formula (1) with a suitable base, such as lithium hydride, lithium N,N-diisopropylamide, sodium hydride, potassium hydride, and potassium t-butoxide. Typically, the reaction is carried out in a substantially anhydrous, aprotic solvent, such as tetrahydrofuran, diethyl ether, dioxane, N-methylpyrrolidinone, N,N-dimethylformamide, N,N-dimethylacetamide, or dimethylsulfoxide. In general, the reaction is carried out at temperatures of from about xe2x88x9220xc2x0 C. to about 70xc2x0 C. The reaction typically requires from about 30 minutes to about 48 hours. The product can be isolated and purified by techniques well known in the art, such as filtration, evaporation, extraction, trituration, chromatography, and crystallization.
Alternately, for example, a compound of formula (1), a compound of formula (axe2x80x2) in which Y is a hydroxy group, a suitable phosphorous(III) compound, and a suitable diester of azodicarboxylate are contacted with under Mitsunobu conditions to give a compound of formula Ixe2x80x2. Such reactions of compounds of formula (1) and compounds of formula (axe2x80x2) in which Y is a hydroxy group are well known in the art. See Synthesis, 1-28 (1981), U.S. Pat. No. 5,821,370, and PCT Publication No. WO 96/38430, published Dec. 5, 1996. The preparation of compounds of formula (axe2x80x2) is well known and appreciated in the art. Suitable phosphorous(III) compounds include, triphenylphosphine, tri(p-tolyl)phosphine, tributylphosphine, and tri(p-dimethylaminiophenyl)phosphine. Suitable diester of azodicarboxylates include diethyl azodicarboxylate, dimethyl azodicarboxylate, diisopropyl azodicarboxylate. Typically, the reaction is carried out in a substantially anhydrous, aprotic solvent, such as tetrahydrofuran, diethyl ether, or dioxane. In general, the reaction is carried out at temperatures of from about 0xc2x0 C. to about 50xc2x0 C. The reaction typically requires from about 30 minutes to about 12 hours. The product can be isolated and purified by techniques well known in the art, such as filtration, evaporation, extraction, trituration, chromatography, and crystallization.
In Reaction Scheme A.1, step d, a protected compound of formula Ixe2x80x2 is deprotected to give a compound of formula I. Deprotection of amine protecting groups is well known and appreciated in the art. Protecting Groups in Organic Synthesis, Theodora Greene (Wiley-Interscience).
In Reaction Scheme A.1, optional step e, not shown, a compound of formula I in which R1 is hydrogen undergoes N-alkylation to give a compound of formula I in which R1 is alkyl, alkenyl, or alkynyl as desired in the final product of formula I and/or a compound of formula I in which R is thioalkyl, thioalkenyl, or thioalkynyl undergoes sulfide oxidation to give a compound of formula I in which R is a sulfoxide or sulfone. Such N-alkylation and oxidation of sulfides are well known and appreciated in the art.
In Reaction Scheme A.1, optional step f, not shown, an acid addition salt is formed using a pharmaceutically-acceptable acid. The formation of acid addition salts is well known and appreciated in the art. 
In Reaction Scheme A.2, step axe2x80x3, depicts the reaction of a suitable alcohol of formula (1) and a suitable compound of formula (axe2x80x3) to give a compound of formula (2). A suitable compound of formula (1) is as described in Reaction Scheme A.1, step axe2x80x2 and a suitable compound of formula (axe2x80x3) is one in which Rxe2x80x2 is a leaving group or gives rise to a leaving group, Rxe2x80x3, in Reaction Scheme A.2, step b. A suitable compound of formula (axe2x80x3) is also one in which Y is a leaving group or a hydroxy group. As is appreciated in the art the compound of formula (2) can be deprotected and again protected, using suitable a protecting group, before it is taken on in Reaction Scheme A.2, step b.
The reaction is carried out as taught in Reaction Scheme A.1, step axe2x80x2, using a compound of formula (axe2x80x3) in which Y is hydroxy, chloro, bromo, iodo, alkylsulfonyl, and the like and Rxe2x80x2 is a leaving group, such as chloro, bromo, iodo, alkylsulfonyl or, preferably, gives rise to a leaving group, such as a thioalkyl group which gives rise to an alkylsulfonyl upon oxidation. Alternately, the reaction is carried out as taught in Reaction Scheme A.1, step axe2x80x2, using a compound of formula (axe2x80x3) in which Y is a hydroxy group and Rxe2x80x2 is a leaving group, such as chloro, bromo, iodo, alkylsufonyl or, preferably, gives rise to a leaving group, such as a thioalkyl group which gives rise to an alkylsulfonyl upon oxidation.
In Reaction Scheme A.2, step b, a compound of formula (2) in which Rxe2x80x2 gives rise to a leaving group, Rxe2x80x3, is converted to a compound of formula (3). As is appreciated by the skilled artisan; where a compound of formula (2) is used in which Rxe2x80x2 is a thioalkyl group which is oxidized to a compound of formula (3) in which Rxe2x80x3 is an alkylsulfonyl, the compound of formula (2) can be protected or can be one which has been deprotected. Thus, the compound of formula (3) prepared in this step can be one in which Rxe2x80x2xe2x80x3 is a suitable protecting group as defined in Reaction Scheme A.1, step axe2x80x2 or can give a compound in which Rxe2x80x2xe2x80x3 is hydrogen.
For example, a compound of formula (2) in which Rxe2x80x2 is a thioalkyl group is contacted with a suitable oxidizing agent to give a compound of formula (3) in which Rxe2x80x2 is an alkylsulfonyl as is well known in the art. For examples see U.S. Pat. No. 5,605,908. Suitable oxidizing agents for this reaction are well known in the art and include oxone(copyright), m-chloroperbenzoic acid, and hydrogen peroxide, oxone(copyright), m-chloroperbenzoic acid, and hydrogen peroxide. Typically, the reaction is carried out in a solvent. Generally, when oxone(copyright) or hydrogen peroxide are used the solvent is water or aqueous mixtures. Generally, when m-chloroperbenzoic acid is used the solvent is an organic solvent, such as dichloromethane, chloroform, and the like. In general, the reaction is carried out at temperatures of from about xe2x88x9220xc2x0 C. to about 50xc2x0 C. The reaction typically requires from about 30 minutes to about 48 hours. The product can be isolated and purified by techniques well known in the art, such as filtration, evaporation, extraction, trituration, chromatography, and crystallization.
Alternately, as is appreciated by those skilled in the art, a compound of formula (3) is readily prepared from the alkoxide of a compound of formula (1) on 3-chloro-4-alkylsulfonyl-1,2,4-thiadiazole as described in U.S. Pat. No. 5,821,370. Such an approach gives a compound of formula (3) in which Rxe2x80x3 is chloro and which are suitable for the reaction depicted in Reaction Scheme A.2, step cxe2x80x2, below.
In Reaction Scheme A.2, step cxe2x80x2, a compound of formula (3) in which Rxe2x80x2xe2x80x3 is a protecting group is contacted with an suitable metal alkoxide or metal thioalkoxide to give a compound of formula Ixe2x80x2. A suitable alkoxide or thioalkoxide is one which give rise to a compound of formula Ixe2x80x2 in which R is xe2x80x94OR2 or xe2x80x94SR2.
For example, a compound of formula (3) is contacted with an suitable metal alkoxide or metal thioalkoxide to give a compound of formula Ixe2x80x2. While many metals are suitable for this reaction, generally, an alkali metal alkoxide or thioalkoxide is used, with the sodium and potassium alkoxide being preferred. The suitable alkoxide or thioalkoxide is formed by contacting an alcohol (HOR2) with a suitable base, such as lithium hydride, sodium hydride, potassium hydride, and potassium t-butoxide or a thiol (HSR2) with a suitable base, such as lithium hydride, sodium hydride, potassium methoxide, sodium methoxide, sodium hydroxide, potassium hydroxide, potassium hydride, and potassium t-butoxide. Typically, the reaction is carried out in a substantially anhydrous, aprotic solvent, such as tetrahydrofuran, dioxane, N-methylpyrrolidinone, N,N-dimethylformamide, N,N-dimethylacetamide, or dimethylsulfoxide. In general, the reaction is carried out at temperatures of from about xe2x88x9220xc2x0 C. to about 70xc2x0 C. The reaction typically requires from about 30 minutes to about 48 hours. The product can be isolated and purified by techniques well known in the art, such as filtration, evaporation, extraction, trituration, chromatography, and crystallization.
In Reaction Scheme A.2, step cxe2x80x3, a compound of formula (3) in which Rxe2x80x2xe2x80x3 is hydrogen is contacted with an suitable metal alkoxide or metal thioalkoxide to give a compound of formula I. A suitable alkoxide or thioalkoxide is as defined in Reaction Scheme A.2, step cxe2x80x2.
In Reaction Scheme A.2, step d, a protected compound of formula Ixe2x80x2 is deprotected as described in Reaction Scheme A.1, step d, above.
In Reaction Scheme A.2, optional step e, not shown, a compound of formula I in which R1 is hydrogen or a compound of formula (3) in which Rxe2x80x2xe2x80x3 is hydrogen undergoes N-alkylation to give a compound of formula I in which R1 is alkyl, alkenyl, or alkynyl as desired in the final product of formula I and/or a compound of formula I in which R is thioalkyl, thioalkenyl, or thioalkynyl undergoes sulfide oxidation to give a compound of formula I in which R is a sulfoxide or sulfone. Such N-alkylation and oxidations of sulfides are well known and appreciated in the art.
In Reaction Scheme A.2, optional step f, not shown, an acid addition salt is formed using a pharmaceutically-acceptable acid. The formation of acid addition salts is well known and appreciated in the art.
The present invention is further illustrated by the following examples and preparations. These examples and preparations are illustrative only and are not intended to limit the invention in any way.